When heart rate increases (as occurs during exercise), coronary blood flow must increase to provide oxygen to the heart to support the augmented myocardial oxygen consumption. The purpose of the proposed research is to discover essential physiological mechanisms that couple coronary blood flow to myocardial oxygen consumption. Without these mechanisms, the heart becomes ischemic and dies. A new hypothesis, with supporting data, is presented where ATP released from red blood cells in the coronary circulation acts as a mediator of local metabolic coronary vasodilation. A plan is presented to quantitatively test the ATP hypothesis during exercise, restricted flow, and anemia with a combination of ATP measurements and ATP-receptor blockade. A second new hypothesis, with supporting data, is presented where deoxyhemoglobin in red blood cells catalyzes the conversion of blood nitrite (NO2-) to nitric oxide (NO) that causes coronary vasodilation. A plan is presented to test the nitrite to nitric oxide hypothesis with nitrite measurements during exercise, restricted flow, and anemia. The unifying concept of this application is that red blood cell hemoglobin acts as an oxygen sensor in the control of coronary blood flow. The two hypotheses explain mechanisms responsible for local metabolic negative feedback control of coronary blood flow. This prevents myocardial ischemia whenever there is an increase in myocardial oxygen consumption. The relevance to public health is that the proposed basic research is fundamental to understanding the normal coronary physiology that underlies coronary artery disease and myocardial ischemia. This is a resubmission of RO1 HL 082781-01-A1 (This time as a modular grant.)